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Retinal arterial occlusion with LIF using rTPA

1999; Elsevier BV; Volume: 106; Issue: 7 Linguagem: Inglês

10.1016/s0161-6420(99)10101-5

1549-4713

Sohan Singh Hayreh,

Cerebral Venous Sinus Thrombosis

Since the first description of central retinal artery occlusion (CRAO) by von Graefe1 in 1859, a host of therapies have been advocated for its treatment and success claimed; however, none of these therapies has stood the test of time. In the April issue, Richard et al2 present their study on local fibrinolysis treatment in 46 eyes with CRAO of 3 to 50 (14 ± 10) hours' duration and 7 eyes with branch retinal artery occlusion (BRAO) and claim that visual acuity improved in 66% of the treated eyes. To evaluate any such study, the first essential is to examine critically the study design and scientific rationale for the therapy used. Experience has shown that the results of a poorly designed study can be misleading and treatments without scientific rationale can be not only useless but also occasionally harmful. Thus, when discussing a study claiming beneficial effects for fibrinolysis therapy in CRAO, one has to consider basic issues, including those discussed below.Problems with the Study Design. This is a retrospective, uncontrolled study, and experience has shown that the results of such studies must be treated with great caution, because of their inherent problems. However, the most important point is that no pretreatment and post-treatment fluorescein fundus angiography was done to document CRAO, the amount of residual retinal circulation (almost invariably seen),3 and any improvement in circulation. This is the most fundamental requirement for any study dealing with retinal circulatory disorder. There is no useful description of the ophthalmologic findings before treatment, 24 hours and 3 months after the occlusion, nor visual field information.Initial Acuity Artifacts. It is not uncommon in CRAO and BRAO to find that the visual acuity at the first visit may be deceptively poor, because the patient, having suddenly lost vision, is in a state of emotional crisis. We know that in these circumstances, the recorded visual acuity is usually much poorer than it truly is. Moreover, in an emergency situation, the testing is not done under ideal conditions. In my studies on CRAO and BRAO, I have seen patients with initial visual acuity recorded by nurses or technicians as only hand motion and, yet, when I tested them shortly thereafter, encouraging eccentric fixation, it was 20/200 or better! In addition, later on, the patient may see much better by learning to fixate eccentrically without any real improvement in the retinal function. In fact, this artifact was responsible for claims of visual improvement with many old therapies that have long been discarded.Natural History of the Disease. In considering the beneficial effects of any treatment, the first absolute essential is to know the natural history of the disease, so that natural recovery is not erroneously attributed to the therapy. My prospective natural history study, done using a strict protocol, of 210 eyes with CRAO and 110 eyes with branch retinal vein occlusion (BRVO), revealed a marked spontaneous visual acuity improvement in a number of patients. Table 1 compares the functionally useful final visual acuity in my natural history study with that reported 3 months after the fibrinolytic treatment by Richard et al.2 The final visual acuity results in the two studies were almost identical. Fibrinolytic therapy did not make any difference. Their claim of 66% improvement in visual acuity in CRAO is misleading because (1) they used only a one-line improvement (which is within the normal variability of testing) as their criterion instead of the two-line or more improvement, which is universally used by scientific studies; and (2) they combined data for visual recovery in CRAO and BRAO, when the initial visual acuity in the seven eyes with BRAO was already 20/30 or better. I have found that in BRAO, if the border between the ischemic and nonischemic retina passes through or near the fovea, there is a spontaneous marked improvement within 3 to 4 weeks.Retinal Tolerance Time to Acute Ischemia. The ischemic penumbra is a well-known phenomenon. Our initial experimental CRAO studies in young rhesus monkeys showed that the retina can survive for approximately 100 minutes without circulation but is permanently damaged by ischemia of 105 minutes or longer.4 Our more recent studies of CRAO in 42 eyes of old rhesus monkeys have shown that if there is a moderate amount of residual circulation in the retina, via the various anastomotic channels of the CRA,5 the retina can survive up to a maximum of 3 to 4 hours. Richard et al2 saw their patients 3 to 50 (average, 14 ± 10) hours after the onset of CRAO, and they claim that 66% of their patients showed visual improvement. They further stressed that eyes with CRAO of even longer than 20 hours can have visual improvement. No scientifically valid study on retinal ischemia supports survival of retina for so long a period. Thus, there is a serious disparity between their claims of visual acuity improvement and what the scientific studies of retinal survival time have shown. Moreover, surprisingly, the authors mention that there was no relationship between the visual outcome and the time lapse between the onset of CRAO and the start of fibrinolysis therapy. This is inconsistent with all scientific studies on retinal ischemia, which have shown that, logically, the longer the period of CRAO beyond the critical period, the more retinal tissue death occurs and the poorer the prognosis becomes.The Effect of Amount of Residual Retinal Circulation on the Visual Outcome after CRAO. Our recent experimental studies on CRAO in 42 old rhesus monkeys have shown that not only the duration of CRAO but also the severity of ischemia influences the visual outcome in CRAO. The latter depends on the amount of residual retinal circulation after CRAO via the multiple anastomoses normally established by the CRA.3,5 Naturally, we realize that the better the circulation, the longer the retina can survive. Therefore, the most critical issue is how much residual circulation each eye in the study by Richard et al2 had before the start of fibrinolysis therapy. Unfortunately, this essential information is completely missing from this study. In its absence, it is impossible to attribute circulatory improvement and visual recovery to fibrinolysis therapy.Causes of CRAO. In my studies of CRAO, I have found that in the majority of patients, the cause of CRAO is embolism, usually from the carotid arteries or the heart. According to the study by Arruga and Sanders,6 the emboli were made of cholesterol in 74%, calcified material in 10.5%, and platelet-fibrin in only 15.5%. Fibrinolytic agents cannot dissolve cholesterol or calcified material, even if they get to the site of occlusion. Therefore, there is no scientific rationale for the use of fibrinolytic agents in approximately 85% of cases. Moreover, when the CRA is completely occluded, there is no flow in the CRA from its site of origin from the ophthalmic artery to the site of occlusion, because there is a static column of blood in that segment of the artery. I do not see how any fibrinolytic agent can reach the site of occlusion in the CRA. The anastomotic channels of the CRA5 only produce flow distal to the site of occlusion toward the retina,3 not backward toward the site of occlusion.Ophthalmic Artery Microcatheterization. Assuming for a moment that this therapy is beneficial, its application has serious limitations. First, the microcatheterization requires the help of a highly expert interventional neuroradiologic group and facilities, which are available at very few places, which seriously limits its usefulness. Second, the authors recorded (1) hemiplegia and (2) occlusion of the ophthalmic artery from a dislodged embolus caused by this procedure. These are serious complications.Systemic and Ocular Complications of Fibrinolytic Therapy. Apart from the two complications recorded by the authors, there is evidence that fibrinolytic therapy is potentially a dangerous therapy, with serious systemic and ocular complications. Two recent multicenter trials7,8 of thrombolytic therapy is acute ischemic stroke showed development of serious complications from thrombolytic therapy and increased morbidity and mortality and concluded that the routine use of this therapy cannot be recommended in acute ischemic stroke. The same warning applies to the use of thrombolytic therapy in CRAO. Richard et al2 stress that the systemic side effects of this therapy can be reduced by local administration of the fibrinolytic agent by microcatheterization of the ophthalmic artery. Even then, I find it hard to justify the life-threatening complications of thrombolytic therapy in CRAO or BRAO, when there is no evident difference in the useful visual outcome compared to the natural history of the disease (Table 1). This is an important ethical issue.